Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097, Paclitaxel, and Carboplatin Before Surgery in Treating Patients With Stage II or Stage III Triple-Negative Breast Cancer
Estrogen Receptor Negative
Progesterone Receptor Negative
Stage IIA Breast Cancer
Stage IIB Breast Cancer
Stage IIIA Breast Cancer
Stage IIIB Breast Cancer
Stage IIIC Breast Cancer
Triple-Negative Breast Carcinoma
Drug: Gamma-Secretase Inhibitor RO4929097
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Procedure: Therapeutic Conventional Surgery
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase 1 Study of Neoadjuvant Chemotherapy With the Gamma Secretase Inhibitor RO4929097 in Combination With Paclitaxel and Carboplatin in Patients With Clinical Stage II-III Triple Negative Breast Cancer|
- Incidence of adverse events of gamma-secretase inhibitor RO4929097 as assessed by CTCAE v 4.0 [ Time Frame: Up to 1 year ] [ Designated as safety issue: Yes ]
- MTD of gamma-secretase inhibitor RO4929097 based on DLT as assessed by CTCAE version (v) 4.0 [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]Analysis will consist of descriptive statistics only. Frequency will be computed for discrete variables with 95% confidence intervals for the proportion.
- Pharmacokinetic parameters of gamma-secretase inhibitor RO4929097 and paclitaxel [ Time Frame: At baseline, at 30, 55, 70 and 90 minutes, and 2, 3, 4, 6, 8 and 24 hours of days 1, 8, 15, and 17 of course 1 ] [ Designated as safety issue: No ]AUC0-24hrs, clearance, maximum concentration, and maximum time (for gamma-secretase inhibitor RO4929097 only) when each drug is administered alone versus when they are co-administered will be compared. Only descriptive statistics will be provided.
|Study Start Date:||December 2010|
|Study Completion Date:||August 2015|
|Primary Completion Date:||January 2014 (Final data collection date for primary outcome measure)|
Experimental: Treatment (RO4929097, paclitaxel, carboplatin, surgery)
Patients receive gamma-secretase inhibitor RO4929097 PO QD on days 1-3, 8-10, and 15-17, paclitaxel IV over 60 minutes on days 1, 8, and 15 (day -1 of course one), and carboplatin IV over 60 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Within 4 weeks after completion of neoadjuvant therapy, patients undergo definitive breast surgery.
Other Names:Drug: Gamma-Secretase Inhibitor RO4929097
Other Name: RO4929097Other: Laboratory Biomarker Analysis
Correlative studiesDrug: Paclitaxel
Other Names:Other: Pharmacological Study
Ancillary studiesProcedure: Therapeutic Conventional Surgery
I. To determine the maximum-tolerated dose (MTD) and dose limiting toxicity (DLT) of RO4929097 (gamma-secretase inhibitor RO4929097) given 3 days on, 4 days off in combination with weekly paclitaxel and every 3 weeks carboplatin that will not cause a 30% or more decrease in paclitaxel area under the plasma-concentration time curve (AUC)0-24hr on day 15 compared to day -1 in patients with clinical stage II-III triple negative breast cancer (TNBC).
I. To measure real-time pharmacokinetics of RO4929097 when administered in combination with weekly paclitaxel and every 3 weeks carboplatin in patients with stage II-III TNBC.
II. To measure real-time pharmacokinetics of paclitaxel when administered in combination with RO4929097 (3 days on, 4 days off) and every 3 weeks carboplatin in patients with stage II-III TNBC.
III. To evaluate the rate of pathologic and clinical complete response to the treatment with combination of RO492097, paclitaxel, and carboplatin in patients with clinical stage II-III TNBC.
OUTLINE: This is a dose-escalation study of gamma secretase inhibitor RO4929097 (RO4929097).
Patients receive gamma-secretase inhibitor RO4929097 orally (PO) once daily (QD) on days 1-3, 8-10, and 15-17, paclitaxel intravenously (IV) over 60 minutes on days 1, 8, and 15 (day -1 of course one), and carboplatin IV over 60 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Within 4 weeks after completion of neoadjuvant therapy, patients undergo definitive breast surgery.
After completion of study treatment, patients are followed up for 1 year.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01238133
|United States, Ohio|
|Ohio State University Comprehensive Cancer Center|
|Columbus, Ohio, United States, 43210|
|Principal Investigator:||Ewa Mrozek||Ohio State University Comprehensive Cancer Center|